Field effectiveness of new visceral leishmaniasis regimens after 1 year following treatment within public health facilities in Bihar, India.
An earlier open label, prospective, non-randomized, non-comparative, multi-centric study conducted within public health facilities in Bihar, India (CTRI/2012/08/002891) measured the field effectiveness of three new treatment regimens for visceral leishmaniasis (VL): single dose AmBisome (SDA), and combination therapies of AmBisome and miltefosine (AmB+Milt) and miltefosine and paromomycin (Milt+PM) up to 6 months follow-up. The National Vector Borne Disease Control Program (NVBDCP) recommended an extended follow up at 12 months post-treatment of the original study cohort to quantify late relapses. The 1,761 patients enrolled in the original study with the three new regimens were contacted and traced between 10 and 36 months following completion of treatment to determine their health status and any occurrence of VL relapse. Of 1,761 patients enrolled in the original study, 1,368 were traced at the extended follow-up visit: 711 (80.5%), 295 (83.2%) and 362 (71.5%) patients treated with SDA, AmB+Milt and Milt+PM respectively. Of those traced, a total of 75 patients were reported to have relapsed by the extended follow-up; 45 (6.3%) in the SDA, 25 (8.5%) in the AmB+Milt and 5 (1.4%) in the Milt+PM arms. Of the 75 relapse cases, 55 had already been identified in the 6-months follow-up and 20 were identified as new cases of relapse at extended follow-up; 7 in the SDA, 10 in the AmB+Milt and 3 in the Milt+PM arms. Extending follow-up beyond the standard 6 months identified additional relapses, suggesting that 12-month sentinel follow-up may be useful as a programmatic tool to better identify and quantify relapses. With limited drug options, there remains an urgent need to develop effective new chemical entities (NCEs) for VL.


Hormone replacement therapy and risk of venous thromboembolism: population based case-control study.
To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism. Population based case-control study. Population enrolled in the General Practice Research Database, United Kingdom. A cohort of 347,253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10,000 controls were randomly selected from the source cohort. Adjusted relative risks estimated from unconditional logistic regression. The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10,000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10,000 women per year. Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.


Biosurfactants as demulsifying agents for oil recovery from oily sludge--performance evaluation.
The oil producing and petroleum refining industries dispose of a significant amount of oily sludge annually. The sludge typically contains a mixture of oil, water and solid particles in the form of complex slurry. The oil in the waste sludge is inextractible due to the complex composition and complex interactions in the sludge matrix. The sludge is disposed of on land or into surface water bodies thereby creating toxic conditions or depleting oxygen required by aquatic animals. In this study, a fumed silica mixture with hydrocarbons was used to facilitate stable emulsion ('Pickering' emulsion) of the oily sludge. The second step of controlled demulsification and separation of oil and sludge into layers was achieved using either a commercial surfactant (sodium dodecyl sulphate (SDS)) or a cost-effective biosurfactant from living organisms. The demulsification and separation of the oil layer using the commercial surfactant SDS was achieved within 4 hours after stopping mixing, which was much faster than the 10 days required to destabilise the emulsion using crude biosurfactants produced by a consortium of petrochemical tolerant bacteria. The recovery rate with bacteria could be improved by using a more purified biosurfactant without the cells.


Visual Semantic Information Pursuit: A Survey.
Visual semantic information comprises two important parts: the meaning of each visual semantic unit and the coherent visual semantic relation conveyed by these visual semantic units. Essentially, the former one is a visual perception task while the latter corresponds to visual context reasoning. Remarkable advances in visual perception have been achieved due to the success of deep learning. In contrast, visual semantic information pursuit, a visual scene semantic interpretation task combining visual perception and visual context reasoning, is still in its early stage. It is the core task of many different computer vision applications, such as object detection, visual semantic segmentation, visual relationship detection, or scene graph generation. Since it helps to enhance the accuracy and the consistency of the resulting interpretation, visual context reasoning is often incorporated with visual perception in current deep end-to-end visual semantic information pursuit methods. Surprisingly, a comprehensive review for this exciting area is still lacking. In this survey, we present a unified theoretical paradigm for all these methods, followed by an overview of the major developments and the future trends in each potential direction. The common benchmark datasets, the evaluation metrics and the comparisons of the corresponding methods are also introduced.


Energy current correlation in solvable long-range interacting systems.
We consider heat transfer in one-dimensional systems with long-range interactions. It is known that typical short-range interacting systems shows anomalous behavior in heat transport when total momentum is conserved, whereas momentum-nonconserving systems do not exhibit anomaly. In this study, we focus on the effect of long-range interaction. We propose an exactly solvable model that reduces to the so-called momentum-exchange model in the short-range interaction limit. We exactly calculate the asymptotic time decay in the energy current correlation function, which is related to the thermal conductivity via the Green-Kubo formula. From the time decay of the current correlation, we show three qualitatively crucial results. First, the anomalous exponent in the time-decay continuously changes as a function of the index of the long-range interaction. Second, there is a regime where the current correlation diverges with increasing the system size with fixed time, and hence, the exponent of the time decay cannot be defined. Third, even momentum-nonconserving systems can show the anomalous exponent indicating anomalous heat transport. Higher dimensions are also considered, and we found that long-range interaction can induce the anomalous exponent even in three-dimensional systems.


Khoisan hunter-gatherers have been the largest population throughout most of modern-human demographic history.
The Khoisan people from Southern Africa maintained ancient lifestyles as hunter-gatherers or pastoralists up to modern times, though little else is known about their early history. Here we infer early demographic histories of modern humans using whole-genome sequences of five Khoisan individuals and one Bantu speaker. Comparison with a 420 K SNP data set from worldwide individuals demonstrates that two of the Khoisan genomes from the Ju/'hoansi population contain exclusive Khoisan ancestry. Coalescent analysis shows that the Khoisan and their ancestors have been the largest populations since their split with the non-Khoisan population ~100-150 kyr ago. In contrast, the ancestors of the non-Khoisan groups, including Bantu-speakers and non-Africans, experienced population declines after the split and lost more than half of their genetic diversity. Paleoclimate records indicate that the precipitation in southern Africa increased ~80-100 kyr ago while west-central Africa became drier. We hypothesize that these climate differences might be related to the divergent-ancient histories among human populations.


Equitable Policies Need Equitable Practices: Alcohol- and Substance-Exposed Pregnancy as a Case Study.
There is clear need for more effective public health policies. Coupled with calls for more effective policies, increasing demand to address public health disparities experienced by systemically marginalized and historically oppressed groups emphasizes the long-standing need for policies that improve public health equity. Such need is highlighted when examining public health issues such as alcohol- and substance-exposed pregnancy (ASEP): Current policies are ineffective at reducing ASEP, and marginalized groups experience disproportionately lower benefits and higher negative consequences as a result of such policies. Powerful strategies to develop more effective policies that can account for the complexity of such issues, such as systems science methods (SSMs), are becoming popular. However, current best practices for such methods often do not emphasize the additional efforts that will be required to develop equitable, not just effective policies. Using ASEP as an example of a crucial complex issue requiring new policy, we suggest additional steps to include in SSM projects for developing more effective policies that will also help stakeholders determine high-equity policies to reduce health disparities. These steps include modeling structural differences experienced by marginalized groups via systemic racism and oppression, incorporating existing cultural and community sources of strength and resilience as key areas for policy development, and evaluating the sustainability of policies as a dimension of efficacy. We also discuss using community-based participatory approaches as a framework for all SSM processes to ensure that policy development itself is grounded in equitable shared decision-making for marginalized individuals.


Productivity measures associated with a patient access initiative.
To assess financial performance associated with a patient 7-day access initiative. Patient access to clinical services is frequently an obstacle at academic medical centers. Conflicting surgeon priorities among academic, clinical, educational, and leadership duties often create difficulties for patient entry into the "system." The scope and objectives were identified to be: design of a standard, simple new patient appointment process, design of a standard process in cases where an appointment is not available in 7 days, use subspecialty team search capabilities, minimize/eliminate prescheduling requirements, centralize appointment scheduling, and creation and reporting of 7-day access metrics. Following maturation of the process, the 7-day access metrics from the period July 2004 to December 2004 and January 2005 to June 2005 were compared with corresponding time periods from calendar years 2001, 2002, and 2003. Payor mix was unaltered. The median waiting time for a new patient appointment decreased from 21 days to 10 days. When compared with calendar years 2001, 2002, and 2003, respectively, the 2 periods of the 7-day access initiative in calendar years 2004 and 2005 were associated with significantly increased visits, new patients, operative procedures, hospital charges, and physician charges. Implementation of a 7-day access initiative can significantly increase financial productivity of general surgery groups in academic medical centers. We conclude that simplifying access to services can benefit academic surgical practices. Sustaining this level of productivity will continue to prove challenging.


Isolation of a cDNA clone encoding a human protein-tyrosine phosphatase with homology to the cytoskeletal-associated proteins band 4.1, ezrin, and talin.
The polymerase chain reaction (PCR), from primers corresponding to conserved sequences within the catalytic domains of the protein-tyrosine phosphatases, was used to amplify protein-tyrosine phosphatase-related cDNAs from a HeLa cell library. After probing the same cDNA library with one of the PCR products, 10 positive clones were identified. The longest of these clones (3984 base pairs) contained 2739 base pairs of open reading frame and, after a stop codon, a 3' nontranslated segment of 1222 base pairs. A 4.3-kilobase transcript was detected by Northern blot analysis of HeLa cell poly(A)+ RNA. The open reading frame predicts a protein of 913 amino acids (approximately 104 kDa), termed PTPH1. The sequence of PTPH1 can be described in terms of three segments. (i) The N-terminal segment displays homology to the domains in the cytoskeletal-associated proteins band 4.1, ezrin, and talin that direct their association with proteins at the interface between the plasma membrane and the cytoskeleton in structures such as focal adhesions. (ii) There is a central segment bearing putative phosphorylation sites for protein-serine/threonine kinases. (iii) A segment that is homologous to the members of the protein-tyrosine phosphatase family is located at the C terminus. The structure is discussed in the light of the potential role of PTPH1 in controlling cytoskeletal integrity and the possibility that overexpression of PTPH1 may reverse transformation induced by oncogenic protein-tyrosine kinases, such as the members of the src family.


Allogeneic chondrogenic-induced mesenchymal stem cells for the treatment of tarsometatarsal lameness in horses.
To assess the efficacy of commercial intra-articular blood-derived allogeneic-induced mesenchymal stem cells (CIMSCs) to treat tarsometatarsal lameness in horses. This was a retrospective cohort study. Records from 167 adult light breed horses with bilateral tarsometatarsal lameness. Horses with tarsometatarsal lameness were retrospectively selected from medical records. Diagnosis followed subjective graded lameness assessment before and after intra-articular analgesia, with graded radiographic tarsal examination. Horses were excluded if they were diagnosed or treated for any other concurrent lameness conditions during the study. Time to last follow-up and time of recurrence of lameness was recorded at veterinary re-assessment. A total of 67 horses were recruited to the CIMSC-treated group and 100 to the corticosteroid (CS)-treated group. Median age was 9 years, with no difference in signalment, use or radiographic grade between groups. First re-examination was 38 days (95% CI: 38-49), with no difference between groups, CIMSC 42 (35-45), control 34 (25-42). Median follow-up was 438 days for CIMSC, 546 for controls. Symptoms of lameness recurred in 86/100 controls compared to 17/67 (25%) CIMSC. Median time to lameness recurring in CIMSC was 336 days (95% CI: 239-400), control 90 days (95% CI: 80-108), p < .0001. Cox proportional hazard ratio for treatment was 8.35, 95% CI: 4.67 to 14.92, p < .0001. Lameness was abolished in all treated horses. It recurred significantly less often, and later, in CIMSC-treated horses. Intra-articular CIMSC treatment results in prolonged soundness in horses with tarsometatarsal lameness.


Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.
Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.


Cardiac ketone body metabolism.
The ketone bodies, d-β-hydroxybutyrate and acetoacetate, are soluble 4-carbon compounds derived principally from fatty acids, that can be metabolised by many oxidative tissues, including heart, in carbohydrate-depleted conditions as glucose-sparing energy substrates. They also have important signalling functions, acting through G-protein coupled receptors and histone deacetylases to regulate metabolism and gene expression including that associated with anti-oxidant activity. Their concentration, and hence availability, increases in diabetes mellitus and heart failure. Whilst known to be substrates for ATP production, especially in starvation, their role(s) in the heart, and in heart disease, is uncertain. Recent evidence, reviewed here, indicates that increased ketone body metabolism is a feature of heart failure, and is accompanied by other changes in substrate selection. Whether the change in myocardial ketone body metabolism is adaptive or maladaptive is unknown, but it offers the possibility of using exogenous ketones to treat the failing heart.


'Spotted Nanoflowers': Gold-seeded Zinc Oxide Nanohybrid for Selective Bio-capture.
Hybrid gold nanostructures seeded into nanotextured zinc oxide (ZnO) nanoflowers (NFs) were created for novel biosensing applications. The selected 'spotted NFs' had a 30-nm-thick gold nanoparticle (AuNP) layer, chosen from a range of AuNP thicknesses, sputtered onto the surface. The generated nanohybrids, characterized by morphological, physical and structural analyses, were uniformly AuNP-seeded onto the ZnO NFs with an average length of 2-3 μm. Selective capture of molecular probes onto the seeded AuNPs was evidence for the specific interaction with DNA from pathogenic Leptospirosis-causing strains via hybridization and mis-match analyses. The attained detection limit was 100 fM as determined via impedance spectroscopy. High levels of stability, reproducibility and regeneration of the sensor were obtained. Selective DNA immobilization and hybridization were confirmed by nitrogen and phosphorus peaks in an X-ray photoelectron spectroscopy analysis. The created nanostructure hybrids illuminate the mechanism of generating multiple-target, high-performance detection on a single NF platform, which opens a new avenue for array-based medical diagnostics.


Electron scattering from pyrazine: elastic differential and integral cross sections.
We report on new measurements for elastic electron scattering from pyrazine. Absolute differential cross sections (DCSs) at seven discrete energies in the range 3-50 eV, and over the scattered electron angular range 10°-129°, were determined using a crossed electron-molecular beam spectrometer in conjunction with the well-established relative flow technique. Integral elastic cross sections were subsequently derived from those DCS data at each energy. Where possible comparison between the present results and those from sophisticated Schwinger multichannel and R-matrix computations is made, with generally quite good quantitative accord being found. Finally, in order to better study some of the rich resonance structure predicted by theory, results from elastic electron excitation functions are presented.


A microliter capillary rheometer for characterization of protein solutions.
Rheometry is an important characterization tool for therapeutic protein solutions because it determines syringeability and relates indirectly to solution stability and thermodynamic interactions. Despite the maturity of rheometry, there remains a need for a rheometer that meets the following three needs of the biopharamaceutical industry: small volume; large dynamic range of shear rates; and no air-sample interface. Here, we report the development of a miniaturized capillary rheometer that meets these needs and is potentially scalable to a multiwell format. These measurements consume only a few microliters of sample and have an uncertainty of a few percent. We demonstrate its performance on monoclonal antibody solutions at different concentrations and temperatures. The instrument has a dynamic range of approximately three decades (in shear rate) and can measure Newtonian, shear thinning, and yielding behaviors, which are representative of the different solution behaviors typically encountered. We compare our microliter capillary rheometer with existing instruments to describe the range of parameter space covered by our device.


The Scientific Study of Consciousness Cannot and Should Not Be Morally Neutral.
A target question for the scientific study of consciousness is how dimensions of consciousness, such as the ability to feel pain and pleasure or reflect on one's own experience, vary in different states and animal species. Considering the tight link between consciousness and moral status, answers to these questions have implications for law and ethics. Here we point out that given this link, the scientific community studying consciousness may face implicit pressure to carry out certain research programs or interpret results in ways that justify current norms rather than challenge them. We show that because consciousness largely determines moral status, the use of nonhuman animals in the scientific study of consciousness introduces a direct conflict between scientific relevance and ethics-the more scientifically valuable an animal model is for studying consciousness, the more difficult it becomes to ethically justify compromises to its well-being for consciousness research. Finally, in light of these considerations, we call for a discussion of the immediate ethical corollaries of the body of knowledge that has accumulated and for a more explicit consideration of the role of ideology and ethics in the scientific study of consciousness.


Hormonal contraceptive use modulates the local inflammatory response to bacterial vaginosis.
To compare cervical concentrations of numerous cytokines/chemokines in women with bacterial vaginosis (BV) compared with the levels detected after BV resolution and determine if hormonal contraceptive use modulates the local inflammatory response to BV. Cervical secretions from 81 women with BV at enrollment and normal flora at one-month follow-up were analysed for 10 different cytokines/chemokines using multiplexed fluorescent bead-based immunoassays. BV was associated with significantly higher concentrations of IL-1 beta, tumour necrosis factor (TNF), interferon-gamma, IL-2, IL-4, and IL-10 compared with the levels detected in the presence of normal vaginal flora. Analysis of results stratified by contraceptive practice demonstrated significantly lower levels of numerous cytokines among women with BV using hormonal contraceptives compared with those women with BV not using hormonal contraceptives. Hormonal contraceptive use was also associated with a statistically significant lesser change in TNF levels between the two study visits compared with the amount of change detected between visits among women who denied their use. Despite increases in the levels of both pro and anti-inflammatory cytokines in the lower genital tract of women with BV, the overall balance of these two types of molecules was maintained. The character of this local inflammatory response may help explain the typical absence of overt signs of inflammation among women with BV. In addition, hormonal contraceptive use was associated with significantly lower levels of the pro-inflammatory molecules TNF, interferon-gamma, and granulocyte macrophage colony-stimulating factor in women with BV, but did not significantly reduce the levels of IL-10, a key anti-inflammatory cytokine. These results suggest the possibility of an association between hormonal contraceptive use and altered genital tract immunity.


Hormonal regulation of root growth: integrating local activities into global behaviour.
To date, plant researchers have probed the control of root growth by studying the roles of individual regulatory components or cellular processes. However, recent studies in the Arabidopsis (Arabidopsis thaliana) root have shown that different hormones control organ growth by regulating specific growth processes (cell proliferation, differentiation or expansion) in distinct tissues. We discuss key issues raised by these new insights and hypothesise that novel tissue-to-tissue signals exist to coordinate organ growth. We conclude by describing how multiscale models can help probe the interplay between the different scales at which hormones and their regulatory networks operate in different cells and tissues. Such approaches promise to generate new insights into the mechanisms that control root growth.


Family history of autoimmune diseases and risk of gastric cancer: a national cohort study.
A personal history of autoimmune diseases is associated with an increased incidence of gastric cancer, but whether they share familial susceptibility is still unknown. The contribution of shared environmental or genetic factors toward the observed familial aggregation has not been determined. We used a few Swedish registers, including the Swedish Multigeneration Register and the Cancer Register, to examine the familial risk of gastric cancer among individuals with a family history of a set of autoimmune diseases. Standardized incidence ratios were used to calculate the relative risk. The overall risk of gastric cancer was 1.22 (95% confidence interval: 1.14-1.30) among individuals with a sibling affected with any of the 33 autoimmune diseases. For specific disease, siblings of individuals with Crohn's diseases, diabetes type 1, Graves'/hyperthyroidism, myasthenia gravis, psoriasis, rheumatoid arthritis, sarcoidosis, and uncreative colitis showed an association with an increased incidence of gastric cancer, with a standardized incidence ratio ranging between 1.17 and 1.64. Familial aggregation was found only for corpus cancer. No association was observed between spouses. Gastric cancer, mainly corpus cancer, shares familial susceptibility with a few autoimmune diseases, suggesting that shared genetic polymorphisms may contribute toward both Helicobacter pylori infection and autoimmune diseases.


Galectin-8 Favors the Presentation of Surface-Tethered Antigens by Stabilizing the B Cell Immune Synapse.
Complete activation of B cells relies on their capacity to extract tethered antigens from immune synapses by either exerting mechanical forces or promoting their proteolytic degradation through lysosome secretion. Whether antigen extraction can also be tuned by local cues originating from the lymphoid microenvironment has not been investigated. We here show that the expression of Galectin-8-a glycan-binding protein found in the extracellular milieu, which regulates interactions between cells and matrix proteins-is increased within lymph nodes under inflammatory conditions where it enhances B cell arrest phases upon antigen recognition in vivo and promotes synapse formation during BCR recognition of immobilized antigens. Galectin-8 triggers a faster recruitment and secretion of lysosomes toward the B cell-antigen contact site, resulting in efficient extraction of immobilized antigens through a proteolytic mechanism. Thus, extracellular cues can determine how B cells sense and extract tethered antigens and thereby tune B cell responses in vivo.


A Comparative Study of the Pharmacokinetics of Clozapine N-Oxide and Clozapine N-Oxide Hydrochloride Salt in Rhesus Macaques.
Translating chemogenetic techniques from nonhuman primates to potential clinical applications has been complicated in part due to in vivo conversion of the chemogenetic actuator, clozapine N-oxide (CNO), to its pharmacologically active parent compound, clozapine, a ligand with known side effects, including five boxed warnings from the Food and Drug Administration. Additionally, the limited solubility of CNO requires high concentrations of potentially toxic detergents such as dimethylsulfoxide (DMSO). To address these concerns, pharmacokinetic profiling of commercially available CNO in DMSO (CNO-DMSO, 10% v/v DMSO in saline) and a water-soluble salt preparation (CNO-HCl, saline) was conducted in rhesus macaques. A time course of blood plasma and cerebrospinal fluid (CSF) concentrations of CNO and clozapine was conducted (30-240 minutes post-administration) following a range of doses (3-10 mg/kg, i.m. and/or i.v.) of CNO-DMSO or CNO-HCl. CNO-HCl resulted in 6- to 7-fold higher plasma concentrations of CNO compared to CNO-DMSO, and relatively less clozapine (3%-5% clozapine/CNO in the CNO-DMSO group and 0.5%-1.5% clozapine/CNO in the CNO-HCl group). Both groups had large between-subjects variability, pointing to the necessity of performing individual CNO pharmacokinetic studies prior to further experimentation. The ratio of CNO measured in the CSF was between 2% and 6% of that measured in the plasma and did not differ across drug preparation, indicating that CSF concentrations may be approximated from plasma samples. In conclusion, CNO-HCl demonstrated improved bioavailability compared with CNO-DMSO with less conversion to clozapine. Further investigation is needed to determine if brain concentrations of clozapine following CNO-HCl administration are pharmacologically active at off-target monoaminergic receptor systems in the primate brain.


Capturing the Onset of PRC2-Mediated Repressive Domain Formation.
Polycomb repressive complex 2 (PRC2) maintains gene silencing by catalyzing methylation of histone H3 at lysine 27 (H3K27me2/3) within chromatin. By designing a system whereby PRC2-mediated repressive domains were collapsed and then reconstructed in an inducible fashion in vivo, a two-step mechanism of H3K27me2/3 domain formation became evident. First, PRC2 is stably recruited by the actions of JARID2 and MTF2 to a limited number of spatially interacting "nucleation sites," creating H3K27me3-forming Polycomb foci within the nucleus. Second, PRC2 is allosterically activated via its binding to H3K27me3 and rapidly spreads H3K27me2/3 both in cis and in far-cis via long-range contacts. As PRC2 proceeds further from the nucleation sites, its stability on chromatin decreases such that domains of H3K27me3 remain proximal, and those of H3K27me2 distal, to the nucleation sites. This study demonstrates the principles of de novo establishment of PRC2-mediated repressive domains across the genome.


Enhanced microvascular relaxations to VEGF and bFGF in chronically ischemic porcine myocardium.
Changes in the vascular responses to vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in chronically ischemic myocardium have not been investigated. Ameroid constrictors were placed on the proximal left circumflex (LCX) artery of seven Yorkshire pigs. Seven to nine weeks later, myocardial blood flow in the collateral-dependent LCX region was reduced, compared with that in the normally perfused left anterior descending (LAD) region. Both growth factors elicited significant relaxations of coronary microvessels. Relaxations to both VEGF and bFGF were inhibited in the presence of either NG-nitro-L-arginine or genistein, suggesting that the relaxations are through the tyrosine kinase-mediated release of endothelium-derived nitric oxide. Microvascular relaxations to both VEGF or bFGF were significantly greater in vessels harvested from the collateral-perfused LCX region, compared with those taken from the normally perfused LAD region. However, relaxation to the endothelium-dependent vasodilator ADP, which does not operate through a tyrosine kinase receptor, was reduced in the collateral-perfused region, compared with the normally perfused territory, suggesting a possible link of tyrosine kinase to the enhanced relaxations to VEGF and bFGF in collateral-perfused coronary microvessels. Northern analysis showed increased expression for both VEGF receptors (flk-1, flt-1) as well as the bFGF receptor 1 (FGFR-1) in the collateral-perfused region compared with that in the normally perfused region. This suggests that the increased relaxation responses to VEGF and bFGF in the ischemic myocardium may be related to increased gene expression of the respective tyrosine kinase receptors.


Multicenter Quality Improvement Project to Prevent Sternal Wound Infections in Pediatric Cardiac Surgery Patients.
Children undergoing cardiac surgery are at risk for sternal wound infections (SWIs) leading to increased morbidity and mortality. Single-center quality improvement (QI) initiatives have demonstrated decreased infection rates utilizing a bundled approach. This multicenter project was designed to assess the efficacy of a protocolized approach to decrease SWI. Pediatric cardiac programs joined a collaborative effort to prevent SWI. Programs implemented the protocol, collected compliance data, and provided data points from local clinical registries using Society of Thoracic Surgery Congenital Heart Surgery Database harvest-compliant software or from other registries. Nine programs prospectively collected compliance data on 4,198 children. Days between infections were extended from 68.2 days (range: 25-82) to 130 days (range: 43-412). Protocol compliance increased from 76.7% (first quarter) to 91.3% (final quarter). Ninety (1.9%) children developed an SWI preprotocol and 64 (1.5%) postprotocol, P = .18. The 657 (15%) delayed sternal closure patients had a 5% infection rate with 18 (5.7%) in year 1 and 14 (4.3%) in year 2 P = .43. Delayed sternal closure patients demonstrated a trend toward increased risk for SWI of 1.046 for each day the sternum remained open, P = .067. Children who received appropriately timed preop antibiotics developed less infections than those who did not, 1.9% versus 4.1%, P = .007. A multicenter QI project to reduce pediatric SWIs demonstrated an extension of days between infections and a decrease in SWIs. Patients who received preop antibiotics on time had lower SWI rates than those who did not.


Ventricular Zone Disruption in Human Neonates With Intraventricular Hemorrhage.
To determine if ventricular zone (VZ) and subventricular zone (SVZ) alterations are associated with intraventricular hemorrhage (IVH) and posthemorrhagic hydrocephalus, we compared postmortem frontal and subcortical brain samples from 12 infants with IVH and 3 nonneurological disease controls without hemorrhages or ventriculomegaly. Birth and expiration estimated gestational ages were 23.0-39.1 and 23.7-44.1 weeks, respectively; survival ranges were 0-42 days (median, 2.0 days). Routine histology and immunohistochemistry for neural stem cells (NSCs), neural progenitors (NPs), multiciliated ependymal cells (ECs), astrocytes (AS), and cell adhesion molecules were performed. Controls exhibited monociliated NSCs and multiciliated ECs lining the ventricles, abundant NPs in the SVZ, and medial vs. lateral wall differences with a complex mosaic organization in the latter. In IVH cases, normal VZ/SVZ areas were mixed with foci of NSC and EC loss, eruption of cells into the ventricle, cytoplasmic transposition of N-cadherin, subependymal rosettes, and periventricular heterotopia. Mature AS populated areas believed to be sites of VZ disruption. The cytopathology and extension of the VZ disruption correlated with developmental age but not with brain hemorrhage grade or location. These results corroborate similar findings in congenital hydrocephalus in animals and humans and indicate that VZ disruption occurs consistently in premature neonates with IVH.


Prevalence and Characteristics of Precore Mutation in Iran and Its Correlation with Genotypes of Hepatitis B.
Mutation of the HBV precore gene prevents the production of HBeAg, which is an important target for immune responses. Distribution of this mutation varies along with frequency of HBV genotypes in accordance with geographic and ethnic variations. The general objective of this study was to evaluate the prevalence and characteristics of precore mutation in Iran and its correlation with genotypes of hepatitis B. In this cross-sectional study, viral DNA of 182 Iranian hepatitis B surface antigen positive patients who were admitted to Bandar Abbas Blood Transfusion Organization in 2012 and 2013 was retrieved from their serum samples. HBeAg, anti-HBe, and anti-HBc IgM diagnostic tests were performed using ELISA kits. Precore and Pre-S regions were amplified using specific primers and PCR thereafter to determine the genotypes; precore mutation, PCR, and restriction fragment length polymorphism (RFLP) methods also were applied. SPSS version 12 was used for data analysis by Mann-Whitney U test, Fisher's exact probability test, and t-test. A total of 62 patients (34.1%) had precore mutation (A1896G), and genotype D was the predominant genotype in these patients, which was followed by an unknown genotype that was suspected for genotype B. Interestingly, the relationships between precore mutation and HBeAg (p=0.037) and genotype D (p=0.005) were significant; however, no correlation was observed between this mutation and acute or chronic hepatitis and sex of patients. This study found high prevalence of precore mutations in southern Iran, which was significantly associated with HBeAg and genotype D.


Once-monthly dosing: an effective step forward.
To improve upon the currently suboptimal level of therapeutic adherence with bisphosphonates in postmenopausal osteoporosis, there is a need to examine less-frequently dosed regimens that offer patients greater convenience than weekly dosing. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for administration with long between-dose intervals. It has proven antifracture efficacy when administered orally, daily or intermittently (>2 months dose-free interval) and a safety profile comparable with placebo. A dose-ranging study evaluating a simplified once-monthly ibandronate dosing schedule confirmed the feasibility of the regimen. Significant decreases from baseline in the biochemical markers of bone turnover, serum and urinary C-telopeptide of the alpha-chain of type 1 collagen (CTX) were observed for all once-monthly doses assessed. An analysis of the area under the effect curve for these two parameters confirmed a dose-response relationship. The MOBILE study was a large (n = 1609), randomized, double-blind, non-inferiority study comparing three doses of monthly oral ibandronate (50 + 50 mg, 100 mg and 150 mg) with daily oral ibandronate (2.5 mg) in women with postmenopausal osteoporosis. Analyses have been completed at the end of 1 and 2 years of treatment. With substantial increases in lumbar spine bone mineral density (BMD; 5.3-6.6%), all of the once-monthly regimens were non-inferior, and, in addition, the 150 mg regimen was superior (P < or = 0.002) to the daily regimen. Corresponding increases in BMD were also observed at all hip sites. The greatest gains in lumbar spine, and hip BMD were consistently seen with the 150 mg regimen. Considerable reductions in serum CTX were seen with all regimens from 3 months onwards (50.0-66.4%); these reductions were maintained throughout the 2-year period (2 years: 56.1-67.7%). The safety profile of the once-monthly regimens was comparable with the daily regimen throughout the 2 years. Once-monthly ibandronate is an effective and well-tolerated treatment for patients with postmenopausal osteoporosis. Given the recently reported strong patient preference for once-monthly regimens and the impact of patient preference on therapeutic adherence, it is anticipated that once-monthly ibandronate will offer patients an alternative convenient regimen that may improve adherence over weekly bisphosphonates and should enhance outcomes.


Nonlinear surface acoustic waves: theory.
A theoretical description is given for the propagation of surface acoustic wave pulses in anisotropic elastic media subject to the influence of nonlinearity. On the basis of nonlinear elasticity theory, an evolution equation is presented for the surface slope or the longitudinal surface velocity associated with an acoustic pulse. It contains a non-local nonlinearity, characterized by a kernel that strongly varies from one propagation geometry to another due to the anisotropy of the substrate. It governs pulse shape evolution in homogeneous halfspaces and the shapes of solitary surface pulses that exist in coated substrates. The theory describing nonlinear Rayleigh-type surface acoustic waves is extended in a straightforward way to surface waves that are localized at a one-dimensional acoustic waveguide like elastic wedges.


Medication Adherence, Burden and Health-Related Quality of Life in Adults with Predialysis Chronic Kidney Disease: A Prospective Cohort Study.
This study examines the associations between medication adherence and burden, and health-related quality of life (HRQOL) in predialysis chronic kidney disease (CKD). A prospective study targeting adults with advanced CKD (estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2) and not receiving renal replacement therapy was conducted in Tasmania, Australia. The actual medication burden was assessed using the 65-item Medication Regimen Complexity Index, whereas perceived burden was self-reported using a brief validated questionnaire. Medication adherence was assessed using a four-item Morisky-Green-Levine Scale (MGLS) and the Tool for Adherence Behaviour Screening (TABS). The Kidney Disease and Quality of Life Short-Form was used to assess HRQOL. Of 464 eligible adults, 101 participated in the baseline interview and 63 completed a follow-up interview at around 14 months. Participants were predominantly men (67%), with a mean age of 72 (SD 11) years and eGFR of 21 (SD 6) mL/min/1.73 m2. Overall, 43% and 60% of participants reported medication nonadherence based on MGLS and TABS, respectively. Higher perceived medication burden and desire for decision-making were associated with nonadherent behaviour. Poorer HRQOL was associated with higher regimen complexity, whereas nonadherence was associated with a decline in physical HRQOL over time. Medication nonadherence, driven by perceived medication burden, was prevalent in this cohort, and was associated with a decline in physical HRQOL over time.


Toward a Values-Informed Approach to Complexity in Health Care: Hermeneutic Review.
Policy Points The concept of value complexity (complexity arising from differences in people's worldviews, interests, and values, leading to mistrust, misunderstanding, and conflict among stakeholders) is introduced and explained. Relevant literature from multiple disciplines is reviewed. Key theoretical themes, including power, conflict, language and framing, meaning-making, and collective deliberation, are identified. Simple rules derived from these theoretical themes are proposed.


CONNECT for better fall prevention in nursing homes: results from a pilot intervention study.
To determine whether an intervention that improves nursing home (NH) staff connections, communication, and problem solving (CONNECT) would improve implementation of a falls reduction education program (FALLS). Cluster randomized trial. Community (n=4) and Veterans Affairs (VA) NHs (n=4). Staff in any role with resident contact (n=497). NHs received FALLS alone (control) or CONNECT followed by FALLS (intervention), each delivered over 3 months. CONNECT used storytelling, relationship mapping, mentoring, self-monitoring, and feedback to help staff identify communication gaps and practice interaction strategies. FALLS included group training, modules, teleconferences, academic detailing, and audit and feedback. NH staff completed surveys about interactions at baseline, 3 months (immediately after CONNECT or control period), and 6 months (immediately after FALLS). A random sample of resident charts was abstracted for fall risk reduction documentation (n=651). Change in facility fall rates was an exploratory outcome. Focus groups were conducted to explore changes in organizational learning. Significant improvements in staff perceptions of communication quality, participation in decision-making, safety climate, caregiving quality, and use of local interaction strategies were observed in intervention community NHs (treatment-by-time effect P=.01) but not in VA NHs, where a ceiling effect was observed. Fall risk reduction documentation did not change significantly, and the direction of change in individual facilities did not relate to observed direction of change in fall rates. Fall rates did not change in control facilities (falls/bed per year: baseline, 2.61; after intervention, 2.64) but decreased by 12% in intervention facilities (falls/bed per year: baseline, 2.34; after intervention, 2.06); the effect of treatment on rate of change was 0.81 (95% confidence interval=0.55-1.20). CONNECT has the potential to improve care delivery in NHs, but the trend toward improving fall rates requires confirmation in a larger ongoing study.


Effects of acute alkalosis and acidosis on performance: a meta-analysis.
Ingestion of agents that modify blood buffering action may affect high-intensity performance. Here we present a meta-analysis of the effects of acute ingestion of three such agents - sodium bicarbonate, sodium citrate and ammonium chloride - on performance and related physiological variables (blood bicarbonate, pH and lactate). A literature search yielded 59 useable studies with 188 observations of performance effects. To perform the mixed-model meta-analysis, all performance effects were converted into a percentage change in mean power and were weighted using standard errors derived from exact p-values, confidence limits (CLs) or estimated errors of measurement. The fixed effects in the meta-analytic model included the number of performance-test bouts (linear), test duration (log linear), blinding (yes/no), competitive status (athlete/nonathlete) and sex (male/female). Dose expressed as buffering mmoL/kg/body mass (BM) was included as a strictly proportional linear effect interacted with all effects except blinding. Probabilistic inferences were derived with reference to thresholds for small and moderate effects on performance of 0.5% and 1.5%, respectively. Publication bias was reduced by excluding study estimates with a standard error >2.7%. The remaining 38 studies and 137 estimates for sodium bicarbonate produced a possibly moderate performance enhancement of 1.7% (90% CL ± 2.0%) with a typical dose of 3.5 mmoL/kg/BM (∼0.3 g/kg/BM) in a single 1-minute sprint, following blinded consumption by male athletes. In the 16 studies and 45 estimates for sodium citrate, a typical dose of 1.5 mmoL/kg/BM (∼0.5 g/kg/BM) had an unclear effect on performance of 0.0% (±1.3%), while the five studies and six estimates for ammonium chloride produced a possibly moderate impairment of 1.6% (±1.9%) with a typical dose of 5.5 mmoL/kg/BM (∼0.3 g/kg/BM). Study and subject characteristics had the following modifying small effects on the enhancement of performance with sodium bicarbonate: an increase of 0.5% (±0.6%) with a 1 mmoL/kg/BM increase in dose; an increase of 0.6% (±0.4%) with five extra sprint bouts; a reduction of 0.6% (±0.9%) for each 10-fold increase in test duration (e.g. 1-10 minutes); reductions of 1.1% (±1.1%) with nonathletes and 0.7% (±1.4%) with females. Unexplained variation in effects between research settings was typically ±1.2%. The only noteworthy effects involving physiological variables were a small correlation between performance and pre-exercise increase in blood bicarbonate with sodium bicarbonate ingestion, and a very large correlation between the increase in blood bicarbonate and time between sodium citrate ingestion and exercise. The approximate equal and opposite effects of sodium bicarbonate and ammonium chloride are consistent with direct performance effects of pH, but sodium citrate appears to have some additional metabolic inhibitory effect. Important future research includes studies of sodium citrate ingestion several hours before exercise and quantification of gastrointestinal symptoms with sodium bicarbonate and citrate. Although individual responses may vary, we recommend ingestion of 0.3-0.5 g/kg/BM sodium bicarbonate to improve mean power by 1.7% (±2.0%) in high-intensity races of short duration.


Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group.
Medulloblastoma is curable in approximately 70% of patients. Over the past decade, progress in improving survival using conventional therapies has stalled, resulting in reduced quality of life due to treatment-related side effects, which are a major concern in survivors. The vast amount of genomic and molecular data generated over the last 5-10 years encourages optimism that improved risk stratification and new molecular targets will improve outcomes. It is now clear that medulloblastoma is not a single-disease entity, but instead consists of at least four distinct molecular subgroups: WNT/Wingless, Sonic Hedgehog, Group 3, and Group 4. The Medulloblastoma Down Under 2013 meeting, which convened at Bunker Bay, Australia, brought together 50 leading clinicians and scientists. The 2-day agenda included focused sessions on pathology and molecular stratification, genomics and mouse models, high-throughput drug screening, and clinical trial design. The meeting established a global action plan to translate novel biologic insights and drug targeting into treatment regimens to improve outcomes. A consensus was reached in several key areas, with the most important being that a novel classification scheme for medulloblastoma based on the four molecular subgroups, as well as histopathologic features, should be presented for consideration in the upcoming fifth edition of the World Health Organization's classification of tumours of the central nervous system. Three other notable areas of agreement were as follows: (1) to establish a central repository of annotated mouse models that are readily accessible and freely available to the international research community; (2) to institute common eligibility criteria between the Children's Oncology Group and the International Society of Paediatric Oncology Europe and initiate joint or parallel clinical trials; (3) to share preliminary high-throughput screening data across discovery labs to hasten the development of novel therapeutics. Medulloblastoma Down Under 2013 was an effective forum for meaningful discussion, which resulted in enhancing international collaborative clinical and translational research of this rare disease. This template could be applied to other fields to devise global action plans addressing all aspects of a disease, from improved disease classification, treatment stratification, and drug targeting to superior treatment regimens to be assessed in cooperative international clinical trials.


First fossil frog from Antarctica: implications for Eocene high latitude climate conditions and Gondwanan cosmopolitanism of Australobatrachia.
Cenozoic ectothermic continental tetrapods (amphibians and reptiles) have not been documented previously from Antarctica, in contrast to all other continents. Here we report a fossil ilium and an ornamented skull bone that can be attributed to the Recent, South American, anuran family Calyptocephalellidae or helmeted frogs, representing the first modern amphibian found in Antarctica. The two bone fragments were recovered in Eocene, approximately 40 million years old, sediments on Seymour Island, Antarctic Peninsula. The record of hyperossified calyptocephalellid frogs outside South America supports Gondwanan cosmopolitanism of the anuran clade Australobatrachia. Our results demonstrate that Eocene freshwater ecosystems in Antarctica provided habitats favourable for ectothermic vertebrates (with mean annual precipitation ≥900 mm, coldest month mean temperature ≥3.75 °C, and warmest month mean temperature ≥13.79 °C), at a time when there were at least ephemeral ice sheets existing on the highlands within the interior of the continent.


Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis.
Congenital heart disease (CHD) accounts for nearly one-third of all major congenital anomalies. CHD birth prevalence worldwide and over time is suggested to vary; however, a complete overview is missing. This systematic review included 114 papers, comprising a total study population of 24,091,867 live births with CHD identified in 164,396 individuals. Birth prevalence of total CHD and the 8 most common subtypes were pooled in 5-year time periods since 1930 and in continent and income groups since 1970 using the inverse variance method. Reported total CHD birth prevalence increased substantially over time, from 0.6 per 1,000 live births (95% confidence interval [CI]: 0.4 to 0.8) in 1930 to 1934 to 9.1 per 1,000 live births (95% CI: 9.0 to 9.2) after 1995. Over the last 15 years, stabilization occurred, corresponding to 1.35 million newborns with CHD every year. Significant geographical differences were found. Asia reported the highest CHD birth prevalence, with 9.3 per 1,000 live births (95% CI: 8.9 to 9.7), with relatively more pulmonary outflow obstructions and fewer left ventricular outflow tract obstructions. Reported total CHD birth prevalence in Europe was significantly higher than in North America (8.2 per 1,000 live births [95% CI: 8.1 to 8.3] vs. 6.9 per 1,000 live births [95% CI: 6.7 to 7.1]; p < 0.001). Access to health care is still limited in many parts of the world, as are diagnostic facilities, probably accounting for differences in reported birth prevalence between high- and low-income countries. Observed differences may also be of genetic, environmental, socioeconomical, or ethnic origin, and there needs to be further investigation to tailor the management of this global health problem.


WITHDRAWN: Amnioinfusion for meconium-stained liquor in labour.
Amnioinfusion aims to prevent or relieve umbilical cord compression during labour by infusing a solution into the uterine cavity. It is also thought to dilute meconium when present in the amniotic fluid and so reduce the risk of meconium aspiration. However, it may be that the mechanism of effect is that it corrects oligohydramnios (reduced amniotic fluid), for which thick meconium staining is a marker. The objective of this review was to assess the effects of amnioinfusion for meconium-stained liquor on perinatal outcome. The Cochrane Pregnancy and Childbirth Group trials register (October 2001) and the Cochrane Controlled Trials Register (Issue 3, 2001) were searched. Randomised trials comparing amnioinfusion with no amnioinfusion for women in labour with moderate or thick meconium-staining of the amniotic fluid. Eligibility and trial quality were assessed by one reviewer. Twelve studies, most involving small numbers of participants, were included. Under standard perinatal surveillance, amnioinfusion was associated with a reduction in the following: heavy meconium staining of the liquor (relative risk 0.03, 95% confidence interval 0.01 to 0.15); variable fetal heart rate deceleration (relative risk 0.65, 95% confidence interval 0.49 to 0.88); and reduced caesarean section overall (relative risk 0.82, 95% confidence interval 0.69 to 1.97). No perinatal deaths were reported. Under limited perinatal surveillance, amnioinfusion was associated with a reduction in the following: meconium aspiration syndrome (relative risk 0.24, 95% confidence interval 0.12 to 0.48); neonatal hypoxic ischaemic encephalopathy (relative risk 0.07, 95% confidence interval 0.01 to 0.56) and neonatal ventilation or intensive care unit admission (relative risk 0.56, 95% confidence interval 0.39 to 0.79); there was a trend towards reduced perinatal mortality (relative risk 0.34, 95% confidence interval 0.11 to 1.06). Amnioinfusion is associated with improvements in perinatal outcome, particularly in settings where facilities for perinatal surveillance are limited. The trials reviewed are too small to address the possibility of rare but serious maternal adverse effects of amnioinfusion.


Context-specific Bayesian clustering for gene expression data.
The recent growth in genomic data and measurements of genome-wide expression patterns allows us to apply computational tools to examine gene regulation by transcription factors. In this work, we present a class of mathematical models that help in understanding the connections between transcription factors and functional classes of genes based on genetic and genomic data. Such a model represents the joint distribution of transcription factor binding sites and of expression levels of a gene in a unified probabilistic model. Learning a combined probability model of binding sites and expression patterns enables us to improve the clustering of the genes based on the discovery of putative binding sites and to detect which binding sites and experiments best characterize a cluster. To learn such models from data, we introduce a new search method that rapidly learns a model according to a Bayesian score. We evaluate our method on synthetic data as well as on real life data and analyze the biological insights it provides. Finally, we demonstrate the applicability of the method to other data analysis problems in gene expression data.


Leveraging big data for improving the estimation of close to reality travel time to obstetric emergency services in urban low- and middle-income settings.
Maternal and perinatal mortality remain huge challenges globally, particularly in low- and middle-income countries (LMICs) where >98% of these deaths occur. Emergency obstetric care (EmOC) provided by skilled health personnel is an evidence-based package of interventions effective in reducing these deaths associated with pregnancy and childbirth. Until recently, pregnant women residing in urban areas have been considered to have good access to care, including EmOC. However, emerging evidence shows that due to rapid urbanization, this so called "urban advantage" is shrinking and in some LMIC settings, it is almost non-existent. This poses a complex challenge for structuring an effective health service delivery system, which tend to have poor spatial planning especially in LMIC settings. To optimize access to EmOC and ultimately reduce preventable maternal deaths within the context of urbanization, it is imperative to accurately locate areas and population groups that are geographically marginalized. Underpinning such assessments is accurately estimating travel time to health facilities that provide EmOC. In this perspective, we discuss strengths and weaknesses of approaches commonly used to estimate travel times to EmOC in LMICs, broadly grouped as reported and modeled approaches, while contextualizing our discussion in urban areas. We then introduce the novel OnTIME project, which seeks to address some of the key limitations in these commonly used approaches by leveraging big data. The perspective concludes with a discussion on anticipated outcomes and potential policy applications of the OnTIME project.


Acute odontogenic infection combined with crowned dens syndrome: a case report.
Calcium pyrophosphate dihydrate crystal deposition disease is a condition in which calcium pyrophosphate dihydrate crystal is deposited in joint cartilage and ligaments. Calcium pyrophosphate dihydrate crystal deposition disease that involves calcification around the odontoid process of the second cervical vertebra is called crowned dens syndrome. Crowned dens syndrome is accompanied by fever in addition to acute and intense neck, posterior head, and temporal pain; thus, distinguishing crowned dens syndrome may be difficult in the presence of odontogenic infection. To the best of our knowledge, this is the first report describing a patient with crowned dens syndrome with coexisting odontogenic infection. A 75-year-old Japanese woman was examined in the Emergency Department of this hospital due to a chief complaint of worsened buccal swelling on the left side. An odontogenic infection was considered, and she underwent her first examination. She presented with a body temperature of 37.4 °C, marked swelling and tenderness of her left lower eyelid through to her left cheek, and pain on the left temporal area. Blood tests revealed a leukocyte count of 6700/μL and a C-reactive protein level of 7.15 mg/dL. There was swelling and pain around the gingiva and acute purulent apical periodontitis of left maxillary second premolar. Cellulitis of the left cheek was diagnosed. After performing drainage of the pus, antibiotic treatment was initiated. Although her clinical symptoms improved, blood tests on day 9 of hospitalization revealed a leukocyte count of 6500/μL and a C-reactive protein level of 25.62 mg/dL, which were indicative of worsening symptoms. Computed tomography was performed to evaluate remote infection and images revealed a calcification around the odontoid process of her second cervical vertebra. When she was referred to the Orthopedic Surgery Department, pseudogout of the cervical spine was diagnosed. Subsequently, oral acetaminophen was initiated, and both her leukocyte count and C-reactive protein improved markedly. In the presence of persistent fever and abnormally high leukocyte and C-reactive protein indicative of an inflammatory reaction, coexistence of pseudogout should be considered. In particular, when symptoms of temporal pain are present, the possibility of pseudogout of the cervical spine must be considered in the differential diagnosis.


Using three-channel video to evaluate the impact of the use of the computer on the patient-centredness of the general practice consultation.
The aim of this study was to assess the feasibility of using three-channel video to explore the impact of the computer on general practitioner (GP) consultations. A previous study had highlighted the limitations of using single-channel video: firstly, there was a lack of information about exactly how the computer was being used, and secondly difficulty in interpreting the body language of the consulting clinician. More information was needed to understand the impact of the computer on the consultation, and in this pilot three-channel video was used to overcome these constraints. Four doctors consulted, with the patient's role played by an actor with a preset script and preloaded personal and family history record programmed into the computer. The output was analysed using the Roter Interaction Analysis System (RIAS) and observational methods were used to explore the effect of computers on aspects of verbal and non-verbal behaviour and the completeness of the computer data record. Three-channel video proved to be a feasible and valuable technique for the analysis of primary care GP consultations, with advantages over single-channel video. Interesting differences in non-verbal and verbal behaviour became apparent with different types of computer use during the consultation. Implications for the three-channel video technique for training, monitoring GP competence and providing feedback are discussed.


Prognostic value of p53 expression in early-stage breast-carcinoma compared with tumor angiogenesis, epidermal growth-factor receptor, C-erbb-2, cathepsin-d, DNA-ploidy, parameters of cell-kinetics and conventional features.
p53 expression detected by immunocytochemistry is emerging as a novel potentially useful prognostic indicator in breast carcinoma. However, additional research is warranted because a consensus has not yet been achieved on: i) methodology and quality control issues; ii) its association with other new biological prognostic indicators; iii) its prognostic value in multivariate analysis including conventional and new pathobiological features and; iv) its clinical usefulness either as a prognostic and predictive factor. This study was undertaken in a series of 165 early-stage breast cancer patients (median follow-up of 5 years) to compare the prognostic role of p53 expression with that of several other markers that have been found to be of value, using a multivariate statistical analysis. These factors are: tumour angiogenesis, epidermal growth factor receptor (EGFR), c-erbB-2 expression, cathepsin D, growth fraction by Ki-67 antibody, DNA ploidy and S-phase fraction. The main results observed were: i) 47 of 165 (28.5%) carcinomas had pAb 1801 staining and were considered as p53-positive; ii) p53 expression was weakly associated with S-phase fraction by flow cytometry (OR=1.86; p=0.085); iii) p53 expression was significantly associated with recurrence (p53 negative [-] versus weak positive [+] tumours: p=0.07 and odds ratio of 2.21; p53 negative [-] versus high positive [++] tumours: p=0.01 and odds ratio of 2.86) and death (p53-versus +: p=0.53 and odds ratio of 1.35; p53- versus ++: p=0.05 and odds ratio of 2.53); iv) the determination of p53 is able to identify a subset of high risk patients in c-erbB-2 negative tumours, this group being generally considered at good prognosis; v) In multivariate analysis on relapse-free survival including all the above markers only tumour angiogenesis, cathepsin D, EGFR and S-phase fraction and nodal status retained significance, and for overall survival only tumour angiogenesis was significant and independent. This new information on p53 expression could be useful to the clinician for a more rationale approach in defining prognosis of breast cancer patients. The prognostic value of p53 depends on which other markers are additionally analyzed and previous studies have not always assayed tumour angiogenesis, which is the most important factor in this series. p53 still need to be assessed as a potential predictor of response to chemo or radiotherapy, because of its role in monitoring DNA damage.


Botulinum toxin A (BT-A) versus low-level laser therapy (LLLT) in chronic migraine treatment: a comparison.
The aim of this work was to evaluate patients with chronic migraine treated with botulinum toxin A (BT-A) and compare this with low level laser therapy (LLLT), referencing: pain days, pain intensity, intake of drugs/self-medication, anxiety and sleep disorders. Patients were randomized into two groups: BT-A group (n = 18) and LLLT group (n = 18). Each patient kept three pain diaries: one before (baseline) (30 days), one during treatment (30 days) and one after the post-treatment phase (30 days). Repeated ANOVA plus the Bonferroni post-test, Student's t test, and factorial analysis were applied, and p < 0.05 was accepted as significant. Our data showed that both treatments were able to reduce headache days, acute medication intake and decrease the intensity of pain. Anxiety was reduced in the BT-A group, while sleep disturbance was reduced in the LLLT group. Our data showed that both treatments can be used to treat chronic migraine, without notable differences between them.


Can Ultrasound Be Used to Predict Loss of Remission in Patients with RA in a Real-life Setting? A Multicenter Cohort Study.
Several studies have suggested that patients with rheumatoid arthritis (RA) presenting with ultrasound (US) synovitis despite clinical remission have more subsequent flares than those who show both clinical and sonographic remission. The objective of our study was to investigate whether these results could be translated to a real-life setting. We compared the time from the first US performed in clinical remission to loss of remission (defined by a DAS28 > 2.6 or the need for stepping up treatment with disease-modifying antirheumatic drugs) within the Swiss Clinical Quality Management cohort of patients with RA, and we adjusted for relevant confounders. Analyses were repeated for different definitions of US-detected synovitis (US+) using greyscale, Doppler, and combined modes based on previously validated scores, and they were adjusted for relevant confounders. There were 318 RA patients with 378 remission phases included. Loss of clinical remission was observed in 60% of remission phases. Residual US synovitis was associated with a shorter duration of clinical remission (median 2-5 mos) and a moderately increased hazard ratio (HR) for loss of remission (HR 1.2-1.5), with the highest HR for the combined US score. The association between US+ and loss of remission was strongest when the US measurement had taken place early in remission (shorter median duration of 6-20 mos) and when followup time was limited to the first 3 or 6 months (most HR between 2-4). US-detected synovitis, particularly when US is performed early in clinical remission, has a moderate predictive power for loss of remission in a real-life setting.


The relationship of right- and left-sided filling pressures in patients with heart failure and a preserved ejection fraction.
Although right-sided filling pressures often mirror left-sided filling pressures in systolic heart failure, it is not known whether a similar relationship exists in heart failure with preserved ejection fraction. Eleven subjects with heart failure with preserved ejection fraction underwent right heart catheterization at rest and under loading conditions manipulated by lower body negative pressure and saline infusion. Right atrial pressure (RAP) was classified as elevated when >or=10 mm Hg and pulmonary capillary wedge pressure (PCWP) when >or=22 mm Hg. If both the RAP and the PCWP were elevated or both not elevated, they were classified as concordant; otherwise, they were classified as discordant. Correlation of RAP and PCWP was determined by a repeated measures model. Among 66 paired measurements of RAP and PCWP, 44 (67%) had a low RAP and PCWP and 8 (12%) a high RAP and PCWP, yielding a concordance rate of 79%. In a sensitivity analysis performed by varying the definition of elevated RAP (from 8 to 12 mm Hg) and PCWP (from 15 to 25 mm Hg), the mean+/-SD concordance of RAP and PCWP was 76+/-10%. The correlation coefficient of RAP and PCWP for the overall cohort was r=0.86 (P<0.0001). Right-sided filling pressures often reflect left-sided filling pressures in heart failure with preserved ejection fraction, supporting the role of estimation of jugular venous pressure to assess volume status in this condition.


Inhibition of human cytomegalovirus DNA polymerase by C-terminal peptides from the UL54 subunit.
In common with other herpesviruses, the human cytomegalovirus (HCMV) DNA polymerase contains a catalytic subunit (Pol or UL54) and an accessory protein (UL44) that is thought to increase the processivity of the enzyme. The observation that antisense inhibition of UL44 synthesis in HCMV-infected cells strongly inhibits viral DNA replication, together with the structural similarity predicted for the herpesvirus processivity subunits, highlights the importance of the accessory protein for virus growth and raises the possibility that the UL54/UL44 interaction might be a valid target for antiviral drugs. To investigate this possibility, overlapping peptides spanning residues 1161 to 1242 of UL54 were synthesized and tested for inhibition of the interaction between purified UL54 and UL44 proteins. A peptide, LPRRLHLEPAFLPYSVKAHECC, corresponding to residues 1221 to 1242 at the very C terminus of UL54, disrupted both the physical interaction between the two proteins and specifically inhibited the stimulation of UL54 by UL44. A mutant peptide lacking the two carboxy-terminal cysteines was markedly less inhibitory, suggesting a role for these residues in the UL54/UL44 interaction. Circular dichroism spectroscopy indicated that the UL54 C-terminal peptide can adopt a partially alpha-helical structure. Taken together, these results indicate that the two subunits of HCMV DNA polymerase most likely interact in a way which is analogous to that of the two subunits of herpes simplex virus DNA polymerase, even though there is no sequence homology in the binding site, and suggest that the UL54 peptide, or derivatives thereof, could form the basis for developing a new class of anti-HCMV inhibitors that act by disrupting the UL54/UL44 interaction.


Global patterns of bacterial beta-diversity in seafloor and seawater ecosystems.
Marine microbial communities have been essential contributors to global biomass, nutrient cycling, and biodiversity since the early history of Earth, but so far their community distribution patterns remain unknown in most marine ecosystems. The synthesis of 9.6 million bacterial V6-rRNA amplicons for 509 samples that span the global ocean's surface to the deep-sea floor shows that pelagic and benthic communities greatly differ, at all taxonomic levels, and share <10% bacterial types defined at 3% sequence similarity level. Surface and deep water, coastal and open ocean, and anoxic and oxic ecosystems host distinct communities that reflect productivity, land influences and other environmental constraints such as oxygen availability. The high variability of bacterial community composition specific to vent and coastal ecosystems reflects the heterogeneity and dynamic nature of these habitats. Both pelagic and benthic bacterial community distributions correlate with surface water productivity, reflecting the coupling between both realms by particle export. Also, differences in physical mixing may play a fundamental role in the distribution patterns of marine bacteria, as benthic communities showed a higher dissimilarity with increasing distance than pelagic communities. This first synthesis of global bacterial distribution across different ecosystems of the World's oceans shows remarkable horizontal and vertical large-scale patterns in bacterial communities. This opens interesting perspectives for the definition of biogeographical biomes for bacteria of ocean waters and the seabed.


Mass spectrometry quantifies protein interactions--from molecular chaperones to membrane porins.
Proteins possess an intimate relationship between their structure and function, with folded protein structures generating recognition motifs for the binding of ligands and other proteins. Mass spectrometry (MS) can provide information on a number of levels of protein structure, from the primary amino acid sequence to its three-dimensional fold and quaternary interactions. Given that MS is a gas-phase technique, with its foundations in analytical chemistry, it is perhaps counter-intuitive to use it to study the structure and non-covalent interactions of proteins that form in solution. Herein we show, however, that MS can go beyond simply preserving protein interactions in the gas phase by providing new insight into dynamic interaction networks, dissociation mechanisms, and the cooperativity of ligand binding. We consider potential pitfalls in data interpretation and place particular emphasis on recent studies that revealed quantitative information about dynamic protein interactions, in both soluble and membrane-embedded assemblies.


Efficacy of sertraline in severe generalized social anxiety disorder: results of a double-blind, placebo-controlled study.
Generalized social anxiety disorder is an early onset, highly chronic, frequently disabling disorder with a lifetime prevalence of approximately 13%. The goal of the current study was to evaluate the efficacy and tolerability of sertraline for the treatment of severe generalized social anxiety disorder in adults. After a 1-week single-blind placebo lead-in period, patients with DSM-IV generalized social phobia were randomly assigned to 12 weeks of double-blind treatment with flexible doses of sertraline (50-200 mg/day) or placebo. Primary efficacy outcomes were the mean change in the Liebowitz Social Anxiety Scale (LSAS) total score and the responder rate for the Clinical Global Impressions-Improvement scale (CGI-I), defined as a CGI-I score </= 2. Data were collected in 2000 and 2001. 211 patients were randomly assigned to sertraline (intent-to-treat [ITT] sample, 205), and 204 patients, to placebo (ITT sample, 196). At week 12, sertraline produced a significantly greater reduction in LSAS total score compared with placebo (mean last-observation-carried-forward [LOCF] change from baseline: -31.0 vs. -21.7; p =.001) and a greater proportion of responders (CGI-I score </= 2: 55.6% vs. 29% among week 12 completers and 46.8% vs. 25.5% in the ITT-LOCF sample; p <.001 for both comparisons). Sertraline was well tolerated, with 7.6% of patients discontinuing due to adverse events versus 2.9% of placebo-treated patients. The results of the current study confirm the efficacy of sertraline in the treatment of severe social anxiety disorder.


Reaction Time Predicts Brain-Computer Interface Aptitude.
There is evidence that 15-30% of the general population cannot effectively operate brain-computer interfaces (BCIs). Thus the BCI performance predictors are critically required to pre-screen participants. Current neurophysiological and psychological tests either require complicated equipment or suffer from subjectivity. Thus, a simple and objective BCI performance predictor is desirable. Neurofeedback (NFB) training involves performing a cognitive task (motor imagery) instructed via sensory stimuli and re-adjusted through ongoing real-time feedback. A simple reaction time (SRT) test reflects the time required for a subject to respond to a defined stimulus. Thus, we postulated that individuals with shorter reaction times operate a BCI with rapidly updated feedback better than individuals with longer reaction times. Furthermore, we investigated how changing the feedback update interval (FUI), i.e., modification of the feedback provision frequency, affects the correlation between the SRT and BCI performance. Ten participants attended four NFB sessions with FUIs of 16, 24, 48, and 96 ms in a randomized order. We found that: 1) SRT is correlated with the BCI performance with FUIs of 16 and 96 ms; 2) good and poor performers elicit stronger ERDs and control BCIs more effectively (i.e., produced larger information transfer rates) with 16 and 96 ms FUIs, respectively. Our findings suggest that SRT may be used as a simple and objective surrogate for BCI aptitude with FUIs of 16 and 96 ms. It also implies that the FUI customization according to participants SRT measure may enhance the BCI performance.


Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease.
Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t((1/2))) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t((1/2)) of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.


Metastatic disease of the spine.
Metastatic spine disease accounts for 10% to 30% of new cancer diagnoses annually. The most frequent presentation is axial pain. A thorough spinal examination includes assessment of local tenderness, deformity, limitation of motion, and signs of nerve root or cord compression. Plain radiographs are obtained routinely; for a suspected or known malignancy, radionuclide studies are essential. Magnetic resonance imaging is more specific than bone scans. Computed tomography-guided biopsy is considered to be safe and accurate for evaluating spinal lesions. Treatment is multidisciplinary, and virtually all treatment is palliative. Management is guided by three key issues: neurologic compromise, spinal instability, and individual patient factors. Site-directed radiation, with or without chemotherapy, is the mainstay of treating painful lesions that are not impinging on neural elements. New data documenting the benefit of surgical decompression using improved techniques such as anterior approaches have amplified the role of the spine surgeon in the care of these patients.


A general likelihood framework for characterizing the time course of neural activity.
We develop a general likelihood-based framework for use in the estimation of neural firing rates, which is designed to choose the temporal smoothing parameters that maximize the likelihood of missing data. This general framework is algorithm-independent and thus can be applied to a multitude of established methods for firing rate or conditional intensity estimation. As a simple example of the use of the general framework, we apply it to the peristimulus time histogram and kernel smoother, the methods most widely used for firing rate estimation in the electrophysiological literature and practice. In doing so, we illustrate how the use of the framework can employ the general point process likelihood as a principled cost function and can provide substantial improvements in estimation accuracy for even the most basic of rate estimation algorithms. In particular, the resultant kernel smoother is simple to implement, efficient to compute, and can accurately determine the bandwidth of a given rate process from individual spike trains. We perform a simulation study to illustrate how the likelihood framework enables the kernel smoother to pick the bandwidth parameter that best predicts missing data, and we show applications to real experimental spike train data. Additionally, we discuss how the general likelihood framework may be used in conjunction with more sophisticated methods for firing rate and conditional intensity estimation and suggest possible applications.


Plasminogen activator inhibitor-1 and relations to fatty acid composition in the diet and in serum cholesterol esters.
High plasminogen activator inhibitor (PAI)-1 levels and poor dietary fat quality are potential risk factors for cardiovascular disease. The aim was to investigate the cross-sectional associations between PAI-1 activity and dietary nutrient intake, focusing on fat quality, in a population-based study of 871 men aged 70 years. The relationship between PAI-1 and the fatty acid composition in serum cholesterol esters (n=381 men) was also studied. The estimated total fat intake was positively associated with PAI-1 activity. The intake of both monounsaturated and polyunsaturated fatty acids was positively associated with PAI-1 activity, whereas the intake of saturated fatty acids was not. In serum cholesterol esters, higher proportions of palmitoleic and dihomo-gamma-linolenic acid, a lower proportion of linoleic acid, and reduced estimated Delta5-desaturase activity were associated with higher PAI-1 levels. These associations were confounded by factors representing the insulin resistance syndrome. PAI-1 activity was positively associated with gamma-linolenic and arachidonic acid, independent of potential confounders. In conclusion, this study demonstrates that dietary intake of unsaturated fatty acids is positively associated with PAI-1 activity, whereas intake of saturated fatty acids is not. The associations present between PAI-1 activity and the fatty acid proportions in serum cholesterol esters are partly influenced by metabolic syndrome-related factors.


Attitudes among healthcare providers and patients diagnosed with sickle cell disease
Sickle cell disease (SCD) is a chronic condition that affects thousands of people worldwide. The purpose of this study is to illustrate some of the challenges and perceptions of people diagnosed with SCD. The aims were to describe stressors, problematic symptoms, sources of support, and interactions with healthcare providers. This descriptive study, using mostly open-ended questions and conceptual analysis, included a sample of patients with SCD who were older than 18 years in ambulatory (57%) and inpatient (43%) clinics. Participants completed a 20-minute interview. Pain or SCD crisis were the chief reasons for hospitalization, and a wellness checkup was the chief reason people returned to an ambulatory clinic. Most (74%) were able to perform chores. Family was reported to cause the most stress in the home and also provide the most help. Pain is a pervasive aspect of life, limiting activities of daily living. Negative interactions with healthcare providers are common; therefore, advocacy is necessary for patients with SCD.


Delay discounting behavior and white matter microstructure abnormalities in youth with a family history of alcoholism.
Youth with family history of alcohol abuse have a greater risk of developing an alcohol use disorder (AUD). Brain and behavior differences may underlie this increased vulnerability. The current study examined delay discounting behavior and white matter microstructure in youth at high risk for alcohol abuse, as determined by a family history of alcoholism (FH+), and youth without such family history (FH-). Thirty-three healthy youth (FH+ = 15, FH- = 18), ages 11 to 15 years, completed a delay discounting task and underwent diffusion tensor imaging. Tract-based spatial statistics (Smith et al., 2006), as well as follow-up region-of-interest analyses, were performed to compare fractional anisotropy (FA) between FH+ and FH- youth. FH+ youth showed a trend toward increased discounting behavior and had significantly slower reaction times (RTs) on the delay discounting paradigm compared to FH- youth. Group differences in FA were seen in several white matter tracts. Furthermore, lower FA in the left inferior longitudinal fasciculus and the right optic radiation statistically mediated the relationship between FH status and slower RTs on the delay discounting task. Youth with a family history of substance abuse have disrupted white matter microstructure, which likely contributes to less efficient cortical processing and may act as an intrinsic risk factor contributing to an increased susceptibility of developing AUD. In addition, FHP youth showed a trend toward greater impulsive decision making, possibly representing an inherent personal characteristic that may facilitate substance use onset and abuse in high-risk youth.


The accuracy of ACTH as a biomarker for pituitary pars intermedia dysfunction in horses: A systematic review and meta-analysis.
Accuracy of baseline ACTH for the diagnosis of PPID in horses varies between studies. To estimate the diagnostic accuracy of ACTH as a biomarker for PPID in adult horses and appraise potential causes of heterogeneity. Systematic review and meta-analysis. A literature review identified studies reporting diagnostic accuracy data for extraction. Risk of bias was evaluated using QUADAS-2. Two random-effects models, the hierarchical summary receiver operating curve (HSROC) and the bivariate binomial normal model (BBN) were used to pool accuracy measurements. We performed meta-regression using study-level variables. The impact of diagnostic test accuracy on the frequency of false-positive and false-negative results at various pretest probabilities was calculated using the BBN model's accuracy results. Patient selection and index test evaluation demonstrated significant risk of bias. Mean and 95% confidence intervals for sensitivity and specificity for all studies (n = 11) based upon the HSROC model were (0.72, 95% CI: 0.62 to 0.82) and (0.88, 95% CI: 0.79 to 0.93), respectively. When studies with a common positivity threshold of 35 pg/mL ACTH were evaluated (n = 6), sensitivity and specificity were (0.66, 95% CI:0.54 to 0.77) and (0.87, 95% CI: 0.74 to 0.94). In a hypothetical group of one thousand horses with PPID prevalence of 2%, 20%, and 90%, the frequency of resulting false-positive and false-negatives would be (127 and 7), (104 and 68) and (13 and 306), respectively. Factors leading to increased accuracy were case-control design, clinical reference standard and data-driven choice of ACTH threshold. A small number of primary studies (n = 11) were available, demonstrating significant biases. Less biased studies examining diagnostic accuracy of ACTH are needed. In horses with a high pretest probability of PPID, ACTH may be a functional "rule-in" test. Baseline ACTH is not recommended for screening purposes or use in horses without clinical signs of PPID.


Grazing patterns in Siphonaria gigas (Mollusca, Pulmonata) on the rocky Pacific coast of Panama.
The pulmonate limpet Siphonaria gigas is the most abundant molluscan grazer in the mid zone on rocky, wave-exposed shores of the Pacific coast of Panama. Erect macroalgae and sessile invertebrates are rare; crustose algae cover ∼90% of the rock. The relative abundance of a common blue-green algal crust (Schizothrix calcicola?) is negatively correlated with Siphonaria's abundance. Large-scale removals of the limpet cause rapid increases in percent cover of Schizothrix and concomitant decreases in other crusts, but no changes in the abundance of erect algae or sessile invertebrates. Removing Siphonaria also (1) increases recruitment of crustose algae and barnacles onto new rock and plexiglass substrata, and (2) decreases the abundance of a calcified form of Schizothrix.Harsh conditions during daytime low tides and foraging by fishes at high tide control the microdistribution of most of this region's mobile and sessile benthic organisms. Wave action and substratum heterogeneity modify these constraints: Siphonaria is rare or absent in sheltered areas, especially on homogeneous surfaces, and is most abundant at wave-exposed sites. However, at extremely wave-beaten sites, Siphonaria and other benthic consumers are rare and ineffective. Crustose algae are reduced in abundance and space is dominated by erect macroalgae and/or barnacles. These normally rare species can outcompete crusts only when thermal or desiccation stress and the effects of benthic consumers and fishes are drastically reduced.


Application of near infrared (NIR) spectroscopy coupled to chemometrics for dried egg-pasta characterization and egg content quantification.
Dried egg pasta is an important and traditional food in the Italian cuisine, and the eggs in pasta improve its nutritional value and organoleptic properties. For this reason the percentage of eggs present in the products sold as "egg pasta" has to always be clearly reported in the label. In this respect, the present research addresses the possibility of developing a method which would allow fast, simple and economic determination of egg content in dried egg-pasta, using near-infrared spectroscopy and chemometric analysis. However, as it is very likely that the spectroscopic fingerprint can also be affected by the manufacturing process of this product, in particular by drying temperature and time, the effect of the manufacturing process on the spectral profile of egg-pasta samples was thoroughly investigated, using experimental design coupled to a multivariate exploratory data analytical technique called ANOVA-Simultaneous Component Analysis (ASCA). Moreover, once confirmed the significance of the drying effect on spectral shape, with the aim of building a calibration model to quantify the egg content in pasta samples irrespective of the manufacturing protocol adopted, a non-linear approach based on local regression, namely LWR-PLS, was investigated. This method allowed the determination of the egg content in external validation samples with low error (RMSEP=1.25), resulting in predictions more accurate and precise than those obtained by a global PLS model.


eHealth Technology Competencies for Health Professionals Working in Home Care to Support Older Adults to Age in Place: Outcomes of a Two-Day Collaborative Workshop.
The demand for care is increasing, whereas in the near future the number of people working in professional care will not match with the demand for care. eHealth technology can help to meet the growing demand for care. Despite the apparent positive effects of eHealth technology, there are still barriers to technology adoption related to the absence of a composite set of knowledge and skills among health care professionals regarding the use of eHealth technology. The objective of this paper is to discuss the competencies required by health care professionals working in home care, with eHealth technologies such as remote telecare and ambient assisted living (AAL), mobile health, and fall detection systems. A two-day collaborative workshop was undertaken with academics across multiple disciplines with experience in working on funded research regarding the application and development of technologies to support older people. The findings revealed that health care professionals working in home care require a subset of composite skills as well as technology-specific competencies to develop the necessary aptitude in eHealth care. This paper argues that eHealth care technology skills must be instilled in health care professionals to ensure that technologies become integral components of future care delivery, especially to support older adults to age in place. Educating health care professionals with the necessary skill training in eHealth care will improve service delivery and optimise the eHealth care potential to reduce costs by improving efficiency. Moreover, embedding eHealth care competencies within training and education for health care professionals ensures that the benefits of new technologies are realized by casting them in the context of the larger system of care. These care improvements will potentially support the independent living of older persons at home. This paper describes the health care professionals' competencies and requirements needed for the use of eHealth technologies to support elderly adults to age in place. In addition, this paper underscores the need for further discussion of the changing role of health care professionals working in home care within the context of emerging eHealth care technologies. The findings are of value to local and central government, health care professionals, service delivery organizations, and commissioners of care to use this paper as a framework to conduct and develop competencies for health care professionals working with eHealth technologies.


Evaluating the evidence for virus/host co-evolution.
There is currently much debate about the timescales of virus evolution. Some viruses may have co-evolved with human populations for tens of thousands of years, or even with our primate ancestors over many millions of years. However, calibrations of the rate of short-term virus evolution lead to estimates of dates for viral ancestors that are orders of magnitude more recent, and a number of the proposed host-virus co-divergence scenarios have been questioned. Other considerations indicate that the proposed recent timescales for virus evolution are implausible, that co-divergence has been rejected prematurely, and that long-term evolutionary rates are very much slower than short-term rates. There is a need to understand the biological basis of this discrepancy and to develop evolutionary models that can accommodate this.


Do fleas affect energy expenditure of their free-living hosts?
Parasites can cause energetically costly behavioural and immunological responses which potentially can reduce host fitness. However, although most laboratory studies indicate that the metabolic rate of the host increases with parasite infestation, this has never been shown in free-living host populations. In fact, studies thus far have shown no effect of parasitism on field metabolic rate (FMR). We tested the effect of parasites on the energy expenditure of a host by measuring FMR using doubly-labelled water in free-living Baluchistan gerbils (Gerbillus nanus) infested by naturally occurring fleas during winter, spring and summer. We showed for the first time that FMR of free-living G. nanus was significantly and positively correlated with parasite load in spring when parasite load was highest; this relationship approached significance in summer when parasite load was lowest but was insignificant in winter. Among seasons, winter FMRs were highest and summer FMRs were lowest in G. nanus. The lack of parasite effect on FMR in winter could be related to the fact that FMR rates were highest among seasons. In this season, thermoregulatory costs are high which may indicate that less energy could be allocated to defend against parasites or to compensate for other costly activities. The question about the cost of parasitism in nature is now one of the major themes in ecological physiology. Our study supports the hypothesis that parasites can elevate FMR of their hosts, at least under certain conditions. However, the effect is complex and factors such as season and parasite load are involved.